Regulation of fat storage and breakdown (lipolysis) in cells and tissues is critical to understanding obesity. Perilipin (peri) proteins, which coat the intracellular lipid droplet in adipocytes, are thought to be critical regulators of fat storage and breakdown since they inhibit lipolysis and in the absence of peri, allow for greater constitutive lipolysis to occur. Peri null (knockout or KO) mice, which do not express perilipin, are resistant to diet-induced obesity (DIO) and lack ectopic fat. Obesity and insulin resistance is associated with increased lipolysis and circulating fatty acids (FA). FA stimulate uncoupling protein-1 (UCP1) activity in the brown adipose tissue (BAT) of rodents resulting in the generation of heat at the expense of the FA. We hypothesize those peri null mice are resistant to DIO due to enhanced constitutive lipolysis, resulting in increased FA flux to BAT and activation of UCPI. Also, we hypothesize that increased metabolism of FA via UCP1 will protect the mice from becoming insulin resistant. The phosphorylation of peri by cyclic-AMP dependent protein kinase A (PKA) abrogates its inhibitory actions on lipases. We have generated our own peri null mice to elucidate peri's actions and in vivo studies to define the critical role of peri and UCP1 in modulating energy metabolism and adipocyte biology. These studies will help us to understand the potentially important role of peri in obesity and its associated complications such as diabetes.